Regulation of vascular contractility and blood pressure by the E2F2 transcription factor

Junlan Zhou, Yan Zhu, Min Cheng, Deepika Dinesh, Tina Thorne, Kian Keong Poh, Dongxu Liu, Chantal Botros, Yao Liang Tang, Nichole Reisdorph, Raj Kishore, Douglas W. Losordo, Gangjian Qin

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11 Scopus citations

Abstract

BACKGROUND-: Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation. METHODS AND RESULTS-: Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2 mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2 mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a,-1c, and-1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays). CONCLUSION-: Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.

Original languageEnglish (US)
Pages (from-to)1213-1221
Number of pages9
JournalCirculation
Volume120
Issue number13
DOIs
StatePublished - Sep 1 2009

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Keywords

  • Blood pressure
  • E2F transcription factors
  • Endothelin
  • Endothelium
  • Mouse
  • Sam68 protein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Zhou, J., Zhu, Y., Cheng, M., Dinesh, D., Thorne, T., Poh, K. K., Liu, D., Botros, C., Tang, Y. L., Reisdorph, N., Kishore, R., Losordo, D. W., & Qin, G. (2009). Regulation of vascular contractility and blood pressure by the E2F2 transcription factor. Circulation, 120(13), 1213-1221. https://doi.org/10.1161/CIRCULATIONAHA.109.859207